Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Differential Association of Serum n-3 Polyunsaturated Fatty Acids with Various Cerebrovascular Lesions in Japanese Men.

BACKGROUND: An association between a high intake of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) with a lower risk of coronary heart disease was previously reported. However, the association between n-3 PUFAs and cerebrovascular lesions remains unclear. We evaluated this association in a general-population-based sample of Japanese men. METHODS: Participants were community-dwelling men (40-79 years old) living in Kusatsu City, Shiga, Japan. Serum concentrations of n-3 PUFAs, defined as the sum of eicosapentaenoic and docosahexaenoic acids, were measured via gas-liquid chromatography between 2006 and 2008. Magnetic resonance imaging was used to assess cerebrovascular lesions (including intracerebral large-artery stenosis, lacunar infarction, and microbleeds) and white matter lesions between 2012 and 2015. Logistic regression adjusting for conventional cardiovascular risk factors was used to estimate the odds ratio of prevalent cerebrovascular lesions per 1 standard deviation higher serum concentration of n-3 PUFAs. RESULTS: Of a total of 739 men, the numbers (crude prevalence in %) of prevalent cerebral large-artery stenoses, lacunar infarctions, microbleeds, and white matter lesions were 222 (30.0), 162 (21.9), 103 (13.9), and 164 (22.2), respectively. A 1 standard deviation higher concentration of n-3 PUFAs (30.5 µmol/L) was independently associated with lower odds of cerebral large-artery stenosis (multivariable-adjusted odds ratio, 0.80; 95% confidential interval, 0.67-0.97). There were no significant associations of n-3 PUFAs with the other types of lesions. CONCLUSIONS: n-3 PUFAs may have protective effects against large-artery stenosis, but not small vessel lesions, in the brain.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.

Association of blood levels of marine omega-3 fatty acids with coronary calcification and calcium density in Japanese men.

BACKGROUND/OBJECTIVES: Clinical trials of eicosapentaenoic acid (EPA) among high-risk groups in Japan in which consumption of mairne-omega-3 fatty acids (OM3) is much higher than other countries showed slower progression of coronary atherosclerosis. We aimed to determine the cross-sectional associations of coronary artery calcification (CAC) and calcium density with OM3, EPA, and docosahexaenoic acid (DHA), two principal OM3, in the general population in Japan. SUBJECTS/METHODS: The Shiga Epidemiological Study of Subclinical Atherosclerosis examined a population-based sample of 1074 men aged 40-79 in 2006-08 for computed tomography-measured CAC score (CCS), a well-established biomarker of coronary atherosclerosis, CAC density score (CDS), a potential marker of plaque stabilization, serum levels of OM3, and risk factors. RESULTS: Prevalence of CCS > 0, ≥ 100, and ≥ 300 was 65.8%, 25.9%, and 12.9%, respectively; the mean (SD) OM3, EPA, and DHA were 10.1% (3.2), 3.2% (1.7), and 5.9% (1.6), respectively. Odds ratios (95% CI, p-value) of CCS 0, 100, and 300 in ordinal logistic regression associated with 1 SD increase of OM3, EPA, and DHA were 0.91 (0.81-1.03, p = 0.12), 0.99 (0.88-1.11, p = 0.87) and 0.84 (0.74-0.94, p = < 0.01), respectively. The inverse association of DHA with CCS remained significant in multivariate-adjusted model: odds ratio of 0.87 (0.77-0.99, p = 0.03). Blood levels of OM3, EPA, or DHA did not have any significant associations with CDS. CONCLUSIONS: DHA but not EPA had a significant inverse association with coronary atherosclerosis in the general population with high levels of OM3. Future trials are warranted comparing the effect of high-dose DHA and EPA on atherosclerosis and cardiovascular outcomes.

Serum magnesium, phosphorus, and calcium levels and subclinical calcific aortic valve disease: A population-based study.

BACKGROUND AND AIMS: Calcific aortic valve disease (CAVD) is the most common valve disease. Although micronutrients are known to contribute to cardiovascular disease, the relationship with CAVD remains poorly evaluated. We examined the association of serum levels of magnesium, phosphorus, and calcium with prevalence, incidence, and progression of aortic valve calcification (AVC). METHODS: We conducted a prospective study in a population-based sample of Japanese men aged 40-79 years without known cardiovascular disease and chronic kidney disease at baseline, and quantified AVC from serial computed tomographic images with the Agatston method. RESULTS: Of 938 participants at baseline (mean age, 63.7 ±â€¯9.9 years), AVC prevalence was observed in 173 (18.4%). Of 596 participants without baseline AVC at follow-up (median duration, 5.1 years), AVC incidence was observed in 138 (23.2%). After adjustment for demographics, behaviors and cardiovascular risk factors, relative risks (95% confidence intervals) in the highest versus lowest categories of serum magnesium, phosphorus, and calcium were 0.62 (0.44-0.86), 1.45 (1.02-2.04), and 1.43 (0.95-2.15), respectively, for AVC prevalence and 0.62 (0.42-0.92), 1.93 (1.28-2.91), and 1.09 (0.77-1.55), respectively, for AVC incidence. Their linear trends of serum magnesium and phosphorus were also all statistically significant. Of 131 participants with baseline AVC, there was no association of any serum micronutrients with AVC progression. CONCLUSIONS: Serum magnesium was inversely associated, while serum phosphorus was positively associated with AVC prevalence and incidence, suggesting that these serum micronutrients may be potential candidates for risk prediction or prevention of CAVD, and warranting further studies.

Significant inverse association of equol-producer status with coronary artery calcification but not dietary isoflavones in healthy Japanese men.

Equol, a metabolite of the dietary isoflavone daidzein, is produced by the action of gut bacteria in some individuals who are termed as equol-producers. It is proposed to have stronger atheroprotective properties than dietary isoflavones. We examined a cross-sectional association of dietary isoflavones and equol-producer status with coronary artery calcification (CAC), a biomarker of coronary atherosclerosis, among men in Japan. A population-based sample of 272 Japanese men aged 40-49 years recruited from 2004 to 2007 was examined for serum isoflavones, serum equol, CAC and other factors. Equol-producers were classified as individuals having a serum level of equol >83 nm. The presence of CAC was defined as a coronary Ca score ≥10 Agatston units. The associations of dietary isoflavones and equol-producers with CAC were analysed using multiple logistic regression. The median of dietary isoflavones, equol and CAC were 512·7 (interquartile range (IQR) 194·1, 1170·0), 9·1 (IQR 0·10, 33·1) and 0·0 (IQR 0·0, 1·0) nm, respectively. Prevalence of CAC and equol-producers was 9·6 and 16·0 %, respectively. Dietary isoflavones were not significantly associated with CAC. After multivariable adjustment, the OR for the presence of CAC in equol-producers compared with equol non-producers was 0·10 (95 % CI 0·01, 0·90, P<0·04). Equol-producers had significantly lower CAC than equol non-producers, but there was no significant association between dietary isoflavones and CAC, suggesting that equol may be a key factor for atheroprotective properties of isoflavones in Japanese men. This finding must be confirmed in larger studies or clinical trials of equol that is now available as a dietary supplement.

Relationship of three different types of low-carbohydrate diet to cardiometabolic risk factors in a Japanese population: the INTERMAP/INTERLIPID Study.

PURPOSE: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations. METHODS: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40-59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA). RESULTS: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = -0.010, P = 0.018). CONCLUSIONS: All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.

High long-chain n-3 fatty acid intake attenuates the effect of high resting heart rate on cardiovascular mortality risk: a 24-year follow-up of Japanese general population.

BACKGROUND: Increased resting heart rate (RHR) independently predicts cardiovascular mortality. Meanwhile, long-chain n-3 fatty acids (LCn3FAs) have a cardioprotective effect. Our aim was to evaluate whether higher LCn3FAs intake attenuates the elevated risk of cardiovascular mortality associated with increased RHR. METHODS: We conducted a population-based 24-year prospective cohort study of Japanese, whose LCn3FAs intake is relatively high. Study participants included 8807 individuals aged 30-95 years from randomly selected areas across Japan without cardiovascular diseases and anti-hypertensive drugs at baseline. The primary endpoint was cardiovascular mortality, and the secondary endpoints were cardiac and stroke mortality during 24 years of follow-up. Individual dietary LCn3FAs intake was estimated from household-based 3-day weighed food records. RHR was obtained from 3 consecutive R-wave intervals on 12-lead electrocardiography. Cox models were used to estimate the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for possible confounders. RESULTS: During the follow-up period, 617 cardiovascular deaths were observed. The median daily intake of LCn3FAs was 0.37% kcal (0.86g/day). The interaction between dietary LCn3FAs intake and RHR in the risk of cardiovascular mortality was statistically significant (p=0.033). The risk of cardiovascular mortality was significantly higher in the low-intake group (<0.37%kcal) with an RHR >85beats/min (bpm) [hazard ratio (HR), 1.67; 95% confidence interval (CI), 1.15-2.43], but not in the high-intake group (≥0.37%kcal) with an RHR >85bpm (HR, 0.92; 95% CI, 0.61-1.38), compared with those in the high-intake group with an RHR <70bpm. Similar results were observed with stroke mortality, but not with cardiac mortality. CONCLUSIONS: The risk of cardiovascular mortality associated with increased RHR is elevated in participants with low dietary LCn3FAs intake, but not in participants with high dietary LCn3FAs intake in a representative Japanese general population. These results suggest that high dietary LCn3FAs intake may prevent cardiovascular mortality associated with increased RHR.

Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.

BACKGROUND: Dietary intake of long-chain n-3 PUFA (LCn3FA) among Japanese is generally higher than that in Western populations. However, little is known whether an inverse association of LCn3FA with cardiovascular disease (CVD) risk exists in a population with higher LCn3FA intake. OBJECTIVE: To investigate the association between LCn3FA intake and the long-term risk of CVDs in a Japanese general population. METHODS: We followed-up a total of 9190 individuals (56.2% women, mean age 50.0 years) randomly selected from 300 areas across Japan and free from CVDs at baseline. Dietary LCn3FA intake was estimated using household weighed food records. Cox models were used to calculate multivariate-adjusted hazard ratios (HR) and confidence intervals (CI) according to sex specific quartiles of LCn3FA intake. RESULTS: During 24-year follow-up (192,897 person-years), 879 cardiovascular deaths were observed. The median daily intake of LCn3FA was 0.37% kcal (0.86 g/day). Adjusted HR for CVD mortality was lower in the highest quartile of LCn3FA intake (HR 0.80; 95% CI 0.66-0.96) compared with the lowest quartile, and the trend was statistically significant (P = 0.038). The similar but statistically non-significant trends were observed for coronary heart disease death and stroke death. In analyses by age groups, the inverse associations of LCn3FA intake with the risk of total CVD death and stroke death were significant in younger individuals (30-59 years at baseline). CONCLUSION: LCn3FA intake was inversely and independently associated the long-term risk of total CVD mortality in a representative sample of Japanese with high LCn3FA intake.

High-density lipoprotein levels have markedly increased over the past twenty years in Japan.

AIM: The high-density lipoprotein cholesterol(HDL-C) level is a major negative risk factor for atherosclerotic diseases dependent on various lifestyle parameters. Changes in the lifestyle of Japanese individuals over the past several decades is believed to have increased their total cholesterol levels and the incidence of cardiovascular disease in Japan. It is therefore important to assess the long-term trends in the HDL-C levels with respect to public health in the community. METHODS: In this study, accumulated data for the serum/plasma HDL-C levels published in cohort studies and obtained during health checkup programs in Japan were analyzed with respect to timedependent changes. RESULTS: The levels of HDL-C have continuously and significantly increased over the past 20 years by 12-15% according to the National Health and Nutrition Study, other cohort studies and commercially available data. On the other hand, the non-HDL-cholesterol levels demonstrated no changes or only a slight decrease during the same period. This finding is consistent with several sets of data obtained from health checkup programs. The commercially measured levels of serum apoA-I, an independent parameter of serum HDL, also showed a similar long-term increase, supporting the above findings. CONCLUSION: We concluded that the serum/plasma HDL concentrations in Japanese individuals, selectively, have increased continuously and significantly over the past 20 years or more. The reasons for this phenomenon and the consequent public health outcomes have yet to be investigated.

Long chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese men in Japan and white men in the USA: population based prospective cohort study.

OBJECTIVE: To determine whether serum concentrations of long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in the incidence rate of coronary artery calcification (CAC) between Japanese men in Japan and white men in the USA. METHODS: In a population based, prospective cohort study, 214 Japanese men and 152 white men aged 40-49 years at baseline (2002-2006) with coronary calcium score (CCS)=0 were re-examined for CAC in 2007-2010. Among these, 175 Japanese men and 113 white men participated in the follow-up exam. Incident cases were defined as participants with CCS≥10 at follow-up. A relative risk regression analysis was used to model the incidence rate ratio between the Japanese and white men. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline. RESULTS: Mean (SD) serum percentage of LCn3PUFA was >100% higher in Japanese men than in white men (9.08 (2.49) vs 3.84 (1.79), respectively, p<0.01). Japanese men had a significantly lower incidence rate of CAC compared to white men (0.9 vs 2.9/100 person-years, respectively, p<0.01). The incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% CI 0.150 to 0.690; p<0.01). After adjusting for age, systolic blood pressure, low density lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant (0.262, 95% CI 0.094 to 0.731; p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376, 95% CI 0.090 to 1.572; p=0.18). CONCLUSIONS: LCn3PUFAs significantly contributed to the difference in the incidence of CAC between Japanese and white men.

Interaction between dietary marine-derived n-3 fatty acids intake and J-point elevation on the risk of cardiac death: a 24-year follow-up of Japanese men.

OBJECTIVE: Higher marine-derived n-3 fatty acids (MDn3FAs) intake reduces the risk of sudden cardiac death via antiarrhythmic effects. The article evaluates whether MDn3FAs intake attenuates the increased risk of cardiac death associated with J-point elevation (JPE), characterised by an elevation of QRS-ST junction (J-point) ≥0.1 mV on electrocardiography. DESIGN: A prospective population-based cohort study. SETTING: The National Survey on Circulatory Disorders and the National Nutrition Survey of Japan. PARTICIPANTS: A total of 4348 community-dwelling men (mean age 49.3 years), without cardiovascular diseases at baseline, from randomly selected areas across Japan. MAIN OUTCOME MEASURES: Cardiac death (200 men) during the 24-year follow-up. RESULTS: Dietary MDn3FAs intake was assessed using a dietary method to estimate individual intake of household-based weighed food records for 3 days. Cox models were used to calculate HRs and 95% CIs adjusted for possible confounding factors. JPE was present in 340 participants (7.8%). The median daily intake of MDn3FAs was 0.35%kcal (0.92 g/day). The risk of cardiac death was significantly higher in participants with JPE than in those without JPE in the low intake group (<0.35%kcal; adjusted HR 3.51; 95% CI 1.84 to 6.73; p<0.001), but not in the high intake group (≥0.35%kcal; adjusted HR 1.09; 95% CI 0.56 to 2.16; p=0.795). The interaction between dietary MDn3FAs intake and JPE on the risk of cardiac death was statistically significant (p=0.006). CONCLUSIONS: The increased risk of cardiac death associated with JPE may be attenuated by higher dietary MDn3FAs intake.

Relationship of dietary monounsaturated fatty acids to blood pressure: the International Study of Macro/Micronutrients and Blood Pressure.

OBJECTIVE: In short-term feeding trials, replacement of other macronutrients with monounsaturated fatty acid reduces blood pressure. However, observational studies have not clearly demonstrated a relationship between monounsaturated fatty acid intake and blood pressure. We report associations of monounsaturated fatty acid intake of individuals with blood pressure in a cross-sectional study. METHODS: The International Study of Macro/Micronutrients and Blood Pressure is a cross-sectional epidemiologic study of 4680 men and women ages 40-59 years from 17 population samples in China, Japan, UK and USA. Nutrient intake data were based on four in-depth multipass 24-h dietary recalls/person and two-timed 24-h urine collections/person. Blood pressure was measured eight times at four visits. RESULTS: Mean monounsaturated fatty acid intake ranged from 8.1%kcal (China) to 12.2%kcal (USA). With sequential models to control for possible confounders (dietary, other), linear regression analyses showed significant inverse relationship of total monounsaturated fatty acid intake with DBP for all participants; for 2238 'nonintervened' individuals, the relationship was stronger. Estimated DBP differences with 2-SD higher monounsaturated fatty acids (5.35%kcal) were -0.82 mmHg (P < 0.05) for all participants and -1.70 mmHg (P < 0.01) for nonintervened individuals. Inverse associations of dietary total oleic acid (main monounsaturated) with blood pressure in nonintervened individuals were not significant, but those of oleic acid from vegetable sources were stronger and significant (P < 0.05). CONCLUSION: Dietary monounsaturated fatty acid intake, especially oleic acid from vegetable sources, may contribute to prevention and control of adverse blood pressure levels in general populations.

A nutrient-wide association study on blood pressure.

BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans--a descriptive epidemiologic study.

In the 1990s Iceland and Japan were known as countries with high fish consumption whereas coronary heart disease (CHD) mortality in Iceland was high and that in Japan was low among developed countries. We described recent data fish consumption and CHD mortality from publicly available data. We also measured CHD risk factors and serum levels of marine-derived n-3 and other fatty acids from population-based samples of 1324 men in Iceland, Japan, South Korea, and the US. CHD mortality in men in Iceland was almost 3 times as high as that in Japan and South Korea. Generally, a profile of CHD risk factors in Icelanders compared to Japanese was more favorable. Serum marine-derived n-3 fatty acids in Iceland were significantly lower than in Japan and South Korea but significantly higher than in the US.

[Effect of cardiovascular risk factors on individual and population medical expenditures: a 10-year cohort study of 4,535 National Health Insurance beneficiaries in Shiga].

A 10-year follow-up cohort study of 4,535 National Health Insurance beneficiaries aged 40 to 69 years in Shiga was performed as part of a research project conducted by the Health Promotion Research Committee of the Shiga National Health Insurance Organizations in 2002. The relationship between cardiovascular risk factors and medical expenditures during the 10-year study period has been examined in this cohort. For example, there was a positively graded correlation between blood pressure and individual total medical expenditures per month. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensives were also higher than those in normotensives. However, from the viewpoint of the entire population, the excess medical expenditures attributable to hypertension within the total medical expenditures were higher for mild-to-moderate hypertensives than for severe hypertensives. On the other hand, although individual medical expenditures per month were 1.7-fold higher for participants with 2 or 3 risk factors and obesity, which was broadly equivalent to metabolic syndrome, than for those without these factors, the excess medical expenditures determined by risk clustering within the total medical expenditures were higher in normal-weight people than in obese people because of the higher prevalence of normal weight. These findings suggest that high-risk individuals are a good target of a high-risk approach, such as intensive health guidance, from the viewpoint of medical expenditures. However, another approach for the majority with a low-to-moderate cardiovascular risk should be considered, because they account for a greater proportion of the excess medical expenditures. Another way to solve this problem may be a population approach with an effective method of providing information to citizens.

Circulating levels of 8 cytokines and marine n-3 fatty acids and indices of obesity in Japanese, white, and Japanese American middle-aged men.

This study examines the differences in circulating levels of cytokines among Japanese in Japan (JJ), Japanese Americans (JA), and whites and their associations with obesity and marine n-3 fatty acids (FA) in a cross-sectional population-based study of 297 men aged 40-49 (100 JJ, 99 whites, and 98 JA). Experimental studies show that cytokines are associated with obesity positively and marine n-3 FA inversely. Serum interleukin-1alpha (IL-1alpha), IL-1 receptor agonist (IL-1ra), IL-4, IL-8, IL-10, inducible protein-10 (IP-10), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and marine n-3 FA were determined. Body mass index (BMI), waist circumference, and computed tomography-measured visceral and subcutaneous adipose tissues were determined. The JJ had significantly lower levels of IL-1alpha, IL-4, IL-8, MCP-1, and TNF-alpha than whites and JA. Whites and JA had similar levels of IL-1alpha, IL-4, and IL-8 whereas whites had significantly higher levels of MCP-1 and TNF-alpha than JA. The JJ were least obese (BMI (kg/m(2)), mean +/- standard deviation) 23.6 +/- 2.8, 27.9 +/- 4.6, and 27.9 +/- 4.5 for JJ, whites, and JA, respectively. The JJ had marine n-3 FA about 100% higher than whites and JA (serum marine n-3 FA (%), median (interquartile range) 8.79 (7.41, 11.16), 3.47 (2.63, 4.83), and 4.44 (3.33, 6.01) for JJ, whites, and JA, respectively). Generally cytokines had weak and nonsignificant associations with indices of obesity and nonsignificant associations with marine n-3 FA. BMI had significant inverse associations with IL-1alpha, IL-4, and IL-8 in JA (P < 0.05). Marine n-3 FA had marginally significant inverse associations with IL-8 in JJ (P = 0.055) and TNF-alpha in whites (P = 0.076). The JJ had lower levels of many cytokines than whites and JA. Generally cytokines had weak and nonsignificant associations with indices of obesity and marine n-3 FA. Further investigation is needed to determine why JJ had lower circulating levels of cytokines.

Medical expenditures of men with hypertension and/or a smoking habit: a 10-year follow-up study of National Health Insurance in Shiga, Japan.

Hypertension and smoking are major causes of disability and death, especially in the Asia-Pacific region, where there is a high prevalence of a combination of these two risk factors. We attempted to measure the medical expenditures of a Japanese male population with hypertension and/or a smoking habit over a 10-year period of follow-up. A cohort study was conducted that investigated the medical expenditures due to a smoking habit and/or hypertension during the decade of the 1990s using existing data on physical status and medical expenditures. The participants included 1708 community-dwelling Japanese men, aged 40-69 years, who were classified into the following four categories: 'neither smoking habit nor hypertension', 'smoking habit alone', 'hypertension alone' or 'both smoking habit and hypertension.' Hypertension was defined as a systolic blood pressure of > or =140 mm Hg, a diastolic blood pressure of > or =90 mm Hg or taking antihypertensive medications. In the study cohort, 24.9% had both a smoking habit and hypertension. During the 10-year follow-up period, participants with a smoking habit alone (18,444 Japanese yen per month), those with hypertension alone (21,252 yen per month) and those with both a smoking habit and hypertension (31,037 yen per month) had increased personal medical expenditures compared with those without a smoking habit and hypertension (17,418 yen per month). Similar differences were observed even after adjustment for other confounding factors (P<0.01). Japanese men with both a smoking habit and hypertension incurred higher medical expenditures compared with those without a smoking habit, hypertension or their combination.

Relationship of the polyunsaturated to saturated fatty acid ratio to cardiovascular risk factors and metabolic syndrome in Japanese: the INTERLIPID study.

AIM: There have been few studies on the relationships of the dietary polyunsaturated to saturated fatty acid ratio (P/S) to cardiovascular risk factors and metabolic syndrome. We hypothesized that there would be favorable relationships. METHODS: Metabolic cardiovascular risk factors from dietary nutrient intake were investigated in 1,004 men and women aged 40-59 years from 4 population samples of Japanese. Multiple linear regression analysis was used to examine the relationship of the dietary P/S ratio to the following risk factors: hemoglobin A1c, blood pressure, serum triglycerides, LDL and total cholesterol, and HDL-cholesterol. Adjusted odds ratio of having metabolic syndrome was also calculated. RESULTS: The dietary P/S ratio was significantly and inversely related to serum total and LDL cholesterol with control for possible confounding variables. We did not find any significant relationship between the P/S ratio and single metabolic risk factors or the prevalence of metabolic syndrome. CONCLUSIONS: Managing the P/S ratio is important to control serum LDL-cholesterol; however, increasing the P/S ratio may not improve metabolic risk factors. Other countermeasures, such as weight control, greater physical activity, and smoking cessation should be recommended to prevent and control metabolic syndrome.

Fatty acids intakes and serum lipid profiles: NIPPON DATA90 and the national nutrition monitoring.

BACKGROUND: The National Nutritional Survey in Japan (NNSJ) was initiated in 1946. Using the majority of the participants for NNSJ, the National Survey on Circulatory Disorders (NSCD) has been conducted every 10 year since 1960. We compared fatty acids intakes obtained from NNSJ and serum lipid profiles from NSCD conducted in 1990. METHODS: A total of 8344 community residents (4856 women and 3488 men, age > or = 30) from 300 randomly selected districts participated in the both surveys in 1990. At baseline, history, physical, and blood biochemical measurement and a nutritional survey were performed. We estimated nutrient intakes of each household member by dividing household intake data proportionally using average intakes by sex and age groups calculated for NNSJ95. RESULTS: Total fat, saturated fatty acids (SFA), poly-unsaturated fatty acids (PUFA), dietary cholesterol, and Keys dietary lipid factor (KEYS) were inversely associated with age in both men and women (all Ps < 0.001). In women, age and body mass index (BMI) adjusted serum total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc) were positively associated with SFA, total fat intakes (%kcal), and with KEYS (P < 0.001). In men, age-BMI adjusted HDLc was not associated with SFA, total fat intakes, and with KEYS factors unlike in women. Other associations were similar to those in women. CONCLUSIONS: The total fatty acids, SFA intakes, and KEYS lipid factor obtained from NNSJ were significantly associated with serum total and LDL cholesterol from the National Survey on Circulatory Disorders conducted in 1990.